During carcinogenesis, the disruption of TGF-beta signaling has been shown to be critical. The underlying mechanisms of resistance to the growth inhibitory effect of TGF-beta in malignant cells involve the altered expression of either the receptors or the signaling molecules. Evidence to date, though, suggests that the most prevalent mechanism involves the receptors. The loss of expression of TGF-beta type II receptor in association with resistance to the growth-inhibitory effect of TGF-beta has been reported in various types of cancers, including gastric and colon cancer. Because the loss of TGF-beta type II receptor expression is frequently observed in many different types of cancers, TGF-beta type II receptor has been proposed to act as a tumor suppressor. Our studies have led to several important observations of mechanisms which inactivate the TGF-beta type II receptor. (i) Transcriptional repression of the TGF-beta type II receptor gene is a major mechanism to inactivate the TGF-beta type II receptor. (ii) The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 gene on chromosome 12p13 in frame with the NTRK3 (TrkC) neurotropin-3 receptor gene on chromosome 15q25. The resultant ETV6-NTRK3 fusion protein is detected in several human cancers including congenital fibrosarcoma and the secretory form of human breast cancer. ETV6-NTRK3 transforms NIH3T3 cells and suppresses TGF-beta type II receptor kinase activity through its interaction with the TGF-beta type II receptor. Another focus of our research has been to identify the cellular proteins that suppress TGF-beta signaling by targeting the Smad proteins. Serum response factor (SRF) is a widely expressed transcription factor involved in immediate early and tissue-specific gene expression, cell proliferation, and differentiation. We defined a new role of SRF as a nuclear repressor of the TGF-beta1 growth inhibitory signal during cell proliferation. We have demonstrated that SRF significantly inhibits the TGF-beta1?}Smad-dependent transcription by associating with Smad3. SRF causes resistance to the TGF-beta1 cytostatic response by directly repressing Smad transcriptional activity, inhibiting formation of the Smad complex and Smad binding to DNA. This leads to the inhibition of expression of TGF-beta1-responsive genes. We have also observed that high expression levels of SRF were detected in primary human gastric cancer tissues. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-beta1 signaling.Overexpression of Smad7 is known to suppress TGF-beta signaling, and is also correlated with poor prognosis in human gastric and hepatocellular carcinomas. However, the role of Smad7 induced by TGF-beta is not well characterized. To elucidate the downstream events of the Smad7-dependent pathway, we performed a yeast two-hybrid screen of human brain cDNA library with Smad7 as a bait. We identified TAK1-binding protein 2 (TAB2) as one of the Smad7-interacting proteins. Upon stimulation by TNF, a proinflammatory cytokine, TAB2 mediates the interaction of TAK1 and TRAF2, and this step is critical for the TNF-mediated NF-kB activation. TGF-beta is a key regulator of inflammation and can inhibit NF-kB activation in certain cell types. However, the exact mechanism by which TGF-beta inhibits NF-kB activation remains unknown. We have demonstrated that Smad7 interacts with TAB2, leading to the blocking of the recruitment of the TAK1 complex to TNFR1 and TRAF2. This interaction results in the suppression of TNF-induced NF-kB transcriptional activity and the sensitization of cells to TNF-mediated apoptosis. These results indicate that pharmacological augmentation of Smad7 expression may be a useful therapeutic strategy in tumors that express high levels of TNF.